Conjugate of podophyllotoxin with chlorambucil: synthesis, biological testing and molecular modeling

   
Zefirov N.A.1 , Mamaeva A.V.2, Radchenko E.V.1, Milaeva E.R.1, Kuznetsov S.A.3, Zefirova O.N.1

1. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia; Institute of Physiologically active compounds, Russian Academy of Sciences, Chernogolovka, Russia
2. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia
3. Institute of Biological Sciences, University of Rostock, Rostock, Germany
Section: Experimental Study
DOI: 10.18097/PBMC20216703289      PubMed Id: 34142536
Year: 2021  Volume: 67  Issue: 3  Pages: 289-294
In the present work we have studied a novel conjugate of the DNA alkylating agent chlorambucil with podophyllotoxin, a ligand of the colchicine binding site in tubulin. The target compound was obtained by Steglich esterification of podophyllotoxin with the percentage yield of 41%. Results of biotesting carried out on the carcinoma A549 cell line revealed that at a concentration of 2 μM the conjugate caused full depolymerization of microtubules without any other effect on free tubulin. The conjugate inhibited proliferation (IC50=135±30 nM) and growth (EC50=240±30 nM) of A549 cells. The data of computer molecular docking of the novel compound into the 3D model of the colchicine binding site in α,β-tubulin and molecular dynamics modelling allowed to explain the observed difference in effects of chlorambucil-podophyllotoxin and chlorambucil-colchicine conjugates on microtubules.
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Keywords: podophyllotoxin, chlorambucil, molecular modeling, tubulin, carcinoma A549
Citation:

Zefirov, N. A., Mamaeva, A. V., Radchenko, E. V., Milaeva, E. R., Kuznetsov, S. A., Zefirova, O. N. (2021). Conjugate of podophyllotoxin with chlorambucil: synthesis, biological testing and molecular modeling. Biomeditsinskaya khimiya, 67(3), 289-294.
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